Research & Scholarship

Current Research and Scholarly Interests

My laboratory research interests are in several areas. Regarding the physiology and pathophysiology of retina and pigment epithelium (RPE), studies have focused on mechanisms that control fluid movement across the RPE, and the adhesion between retina and RPE. We have also studied the modification of retinal ischemic damage, laser action upon the RPE and drug effects upon retina and RPE. Recent collaborative work has been considering means of replacing Bruch's membrane or RPE in diseased eyes, and the development of a retinal prosthesis.

Clinical investigations cover several areas. We are studying electrophysiological tests of retinal and RPE function, including non-photic responses (induced by drugs) and newer electroretinographic techniques such as multifocal ERG recording. Unusual dystrophies, toxic retinopathies and clinical problems in the area of medical retinal disorders are evaluated as appropriate. The pathophysiology of central serous chorioretinopathy has been studied. Our research programs bear directly on blinding disorders such as age-related macular degeneration, vascular disease (including diabetes), retinal detachment, retinitis pigmentosa, macular dystrophies and toxic retinopathies.

Another major area of interest is the relationship between human vision and art, music, history, literature and sport. The role and implications of vision in art have been studied in depth.

Abstract

Hydroxychloroquine sulfate retinopathy can progress after the drug is stopped. It is not clear how this relates to the stage of retinopathy or whether early screening with modern imaging technology can prevent progression and visual loss.To determine the relationship between progression of retinopathy and the severity of disease using objective data from optical coherence tomography and assess the value of early screening for the toxic effects of hydroxychloroquine.Clinical findings in patients with hydroxychloroquine retinopathy were monitored with repeated anatomical and functional examinations for 13 to 40 months after the drug was stopped in a referral practice in a university medical center. Eleven patients participated, with the severity of toxic effects categorized as early (patchy parafoveal damage shown on field or objective testing), moderate (a 50%-100% parafoveal ring of optical coherence tomography thinning but intact retinal pigment epithelium), and severe (visible bull's-eye damage).Visual acuity, white 10-2 visual field pattern density plots, fundus autofluorescence, spectral-density optical coherence tomography cross sections, thickness (from cube diagrams), and ellipsoid zone length.Visual acuity and visual fields showed no consistent change. Fundus autofluorescence showed little or no change except in severe cases in which the bull's-eye damage expanded progressively. Optical coherence tomography cross sections showed little visible change in early and moderate cases but progressive foveal thinning (approximately 7 μm/y) and loss of ellipsoid zone (in the range of 100 μm/y) in severe cases, which was confirmed by quantitative measurements. The measurements also showed some foveal thinning (approximately 4 μm/y) and deepening of parafoveal loss in moderate cases, but the breadth of the ellipsoid zone remained constant in both early and moderate cases. A few cases showed a suggestion of ellipsoid zone improvement.Patients with hydroxychloroquine retinopathy involving the retinal pigment epithelium demonstrated progressive damage on optical coherence tomography for at least 3 years after the drug was discontinued, including loss of foveal thickness and cone structure. Cases recognized before retinal pigment epithelium damage retained foveal architecture with little retinal thinning. Early recognition of hydroxychloroquine toxic effects before any fundus changes are visible, using visual fields and optical coherence tomography (along with fundus autofluorescence and multifocal electroretinography as indicated), will greatly minimize late progression and the risk of visual loss.

Abstract

American Academy of Ophthalmology recommendations for screening for hydroxychloroquine (HCQ) retinopathy advise objective measures, such as spectral-domain optical coherence tomography (SD-OCT) and multifocal electroretinography (mfERG) along with visual fields. However, the relative sensitivity and specificity of screening tests have not been fully resolved. We characterize a subset of patients with toxicity who show unusual disparity between fields and SD-OCT and thus have implications for screening practice.Review of charts and clinical data.Patients at Stanford and Kaiser Permanente who had used HCQ with greater than 1000 g cumulative exposure. There were more than 2000 such individuals, among whom 150 had clear evidence of toxicity.Patients were evaluated by visual fields (10-2 white Swedish Interactive Threshold Algorithm pattern deviation plots), SD-OCT, and sometimes mfERG or fundus autofluorescence.Relative findings on visual fields in comparison with SD-OCT.There were 11 patients among those with HCQ toxicity who had parafoveal ring scotomas but a normal-appearing SD-OCT. None had a history of macular disease or evidence for any other cause of bull's eye maculopathy. Conversely, all cases with a clear degree of parafoveal damage on SD-OCT showed at least some focal spots of parafoveal field loss.Approximately 10% of patients with early HCQ toxicity showed prominent ring scotomas on field testing without obvious SD-OCT abnormality. This should encourage the inclusion of visual fields as a key screening tool, even when SD-OCT (a more specific and objective test) also is performed. The combination of visual fields and SD-OCT gives both sensitivity and specificity while avoiding unnecessary stoppage of the drug.

Abstract

The French Impressionist painter Edgar Degas had progressive visual loss from a type of maculopathy during the last 40 years of his life. The effects of this visual failure are evident in a comparison of early and later pastels, which shows a loss of precision in outlining, shading, and detail over the years. A remarkable oil painting, Scene from the Steeplechase: The Fallen Jockey, provides on one canvas an historical record of his visual struggles. It was begun in 1866 and reworked in 1880 and 1897, during which his visual acuity fell from near normal to 20/200. Computer simulations show Degas' own view of this painting at each of these times and demonstrate how his style changed: details became rougher and larger in correspondence with his failing acuity. The painting is an eye chart of his career.

Abstract

To compare the value of red vs white 10-2 visual field testing in patients with different levels of hydroxychloroquine exposure and retinopathy in reference to recent American Academy of Ophthalmology recommendations on screening for hydroxychloroquine retinopathy that advised the use of 10-2 visual field testing with a white test object.We studied retrospectively 13 patients using hydroxychloroquine who had undergone both red (FASTPAC) and white (SITA) 10-2 automated visual field testing in the course of their management. On clinical grounds, they were judged to have no retinopathy, early retinopathy, or moderate or severe hydroxychloroquine retinopathy.White visual field diagrams were difficult to interpret, but pattern deviation plots consistently showed parafoveal sensitivity losses in early retinopathy. Red fields often showed more prominent scotomas in early retinopathy but sometimes showed irregular losses that were hard to evaluate. Either modality showed clear losses in moderate retinopathy. On repeated testing, the pattern deviation plots were somewhat more consistent than red fields in showing parafoveal damage.With white 10-2 visual field hydroxychloroquine screening, the use of pattern deviation plots should be standard practice. Red testing appears to be more sensitive for early retinopathy but may be slightly less specific or consistent. We believe the main application for red testing is in screening for the earliest signs of retinopathy. Either red or white fields should be acceptable for hydroxychloroquine screening, as long as the clinician is sensitive to the characteristic patterns of early parafoveal damage and is prepared to retest fields and add objective tests.

Abstract

To develop a method for modulation of transgene expression in retinal pigment epithelium (RPE) using scanning laser that spares neurosensory retina.Fifteen pigmented rabbits received subretinal injection of recombinant adeno-associated virus (rAAV-2) encoding green fluorescent protein (GFP). GFP expression was measured using confocal scanning laser ophthalmoscopy (cSLO) fluorescence imaging and immunohistochemistry. To reduce the total expression in RPE by half, 50% of the transfected RPE cells were selectively destroyed by microsecond exposures to scanning laser with 50% pattern density. The selectivity of RPE destruction and its migration and proliferation were monitored using fluorescein angiography, spectral-domain optical coherence tomography (SD-OCT), and light, transmission, and scanning electron microscopy. 5-Bromo-2'-dioxyuridine (BrdU) assay was performed to evaluate proliferation of RPE cells.RPE cells were selectively destroyed by the line scanning laser with 15 μs exposures, without damage to the photoreceptors or Bruch's membrane. RPE cells started migrating after the first day, and in 1 week there was complete restoration of RPE monolayer. Selective laser treatment decreased the GFP fluorescence by 54% as compared to control areas; this was further decreased by an additional 48% following a second treatment 1 month later. BrdU assay demonstrated proliferation in approximately half of the RPE cells in treatment areas.Microsecond exposures produced by scanning laser destroyed RPE cells selectively, without damage to neural retina. Continuity of RPE layer is restored within days by migration and proliferation, but transgene not integrated into the nucleus is not replicated. Therefore, gene expression can be modulated in a precise manner by controlling the laser pattern density and further adjusted using repeated applications.

Abstract

To describe a distinctive foveal cavitation as seen by spectral-domain optical coherence tomography in certain cone dysfunction syndromes.Observational case series. Patients were evaluated by dilated fundus examination, fundus photography, fundus autofluorescence, full-field electroretinogram, multifocal electroretinogram, spectral-domain optical coherence tomography, color vision testing, fluorescein angiography, Goldmann visual field testing, and molecular genetic analysis.We present eight patients with foveal cavitation in association with presumed cone dysfunction. This was characterized on spectral-domain optical coherence tomography by a gap in the subfoveal outer segment layer without more diffuse retinal thinning. There were 5 patients of age 10 years to 27 years and 3 patients of age 49 years to 52 years, with a 1.5- to 38-year history of bilateral visual loss. A small foveal oval-shaped area of reduced foveal fundus autofluorescence, surrounded by increased fundus autofluorescence, was seen in the younger patients, and a broad circle of increased fundus autofluorescence in the older patients. The multifocal electroretinogram always showed central amplitude reduction, but there were varying degrees of cone dysfunction on full-field electroretinogram. There were mild abnormalities on desaturated color vision testing. The family history was noncontributory in all cases. None of the cases were congenital. ABCA4 gene mutations were identified in three of five patients tested; CNGB3 testing was negative in these patients.Cone dysfunction syndromes typically show retinal thinning on optical coherence tomography imaging, although several case reports have noted focal outer retinal loss. Our case series shows that a distinctive optical coherence tomography finding, foveal cavitation, may be a clue to cone dysfunction syndromes, but is not specific to any one hereditary disorder or age group.

Abstract

To compare different screening procedures for hydroxychloroquine sulfate (Plaquenil) toxicity at different stages of damage.Ten patients were studied using 10-2 automated fields, multifocal electroretinography, spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence.All 10 patients used hydroxychloroquine for more than 6 years, and those with severe toxicity had been overdosed. Fundus examination findings were normal except for the patients with severe toxicity. All the patients showed parafoveal field loss, but this was sometimes subtle. Multifocal electroretinography demonstrated parafoveal weakness in the milder cases. The SD-OCT subfield thickness plots showed a ring of parafoveal thinning in all the patients. The SD-OCT cross-sections showed parafoveal loss of the inner segment-outer segment and cone outer segment tip lines at early stages of toxicity, progressing to parafoveal thinning of the outer nuclear layer and eventually to retinal pigment epithelium damage. There was a ring of autofluorescence in most patients.Overdosage with hydroxychloroquine seemed a significant risk factor for toxicity. Different individuals were more or less sensitive to different tests. Fields can be sensitive but only if read with a low threshold for change. Hydroxychloroquine causes early parafoveal loss of the outer segment lines on SD-OCT, with the first changes often evident in the inferotemporal quadrant. Parafoveal thinning of the outer nuclear layer follows, before retinal pigment epithelium damage is visible. Careful screening with multiple tests can detect toxic damage before prominent loss of the outer nuclear layer.

Abstract

The clinical multifocal electroretinogram (mfERG) is an electrophysiological test of local retinal function. With this technique, many local ERG responses are recorded quasi-simultaneously from the cone-driven retina under light-adapted conditions. This document, from the International Society for Clinical Electrophysiology of Vision (ISCEV: www.iscev.org ), replaces the ISCEV guidelines for the mfERG published in 2007. Standards for performance of the basic clinical mfERG test with a stimulus array of 61 or 103 hexagons, as well as for reporting the results, are specified.

Abstract

It has been 50 years since fluorescein angiography was developed as a clinical procedure by 2 medical students at Indiana University. The story of its discovery and the recognition of its value to ophthalmology involve a combination of insight and serendipity. Fluorescein had been in use clinically for more than half a century, but it took a pulmonary medicine laboratory to provide the stimulus for the development of flash and barrier filters that would make vascular photography practical. The first article was rejected by the ophthalmology literature, but several clinics heard about it and soon documented the enormous diagnostic value of the procedure.

Abstract

The American Academy of Ophthalmology recommendations for screening of chloroquine (CQ) and hydroxychloroquine (HCQ) retinopathy were published in 2002, but improved screening tools and new knowledge about the prevalence of toxicity have appeared in the ensuing years. No treatment exists as yet for this disorder, so it is imperative that patients and their physicians be aware of the best practices for minimizing toxic damage. RISK OF TOXICITY: New data have shown that the risk of toxicity increases sharply toward 1% after 5 to 7 years of use, or a cumulative dose of 1000 g, of HCQ. The risk increases further with continued use of the drug. DOSAGE: The prior recommendation emphasized dosing by weight. However, most patients are routinely given 400 mg of HCQ daily (or 250 mg CQ). This dose is now considered acceptable, except for individuals of short stature, for whom the dose should be determined on the basis of ideal body weight to avoid overdosage. SCREENING SCHEDULE: A baseline examination is advised for patients starting these drugs to serve as a reference point and to rule out maculopathy, which might be a contraindication to their use. Annual screening should begin after 5 years (or sooner if there are unusual risk factors). SCREENING TESTS: Newer objective tests, such as multifocal electroretinogram (mfERG), spectral domain optical coherence tomography (SD-OCT), and fundus autofluorescence (FAF), can be more sensitive than visual fields. It is now recommended that along with 10-2 automated fields, at least one of these procedures be used for routine screening where available. When fields are performed independently, even the most subtle 10-2 field changes should be taken seriously and are an indication for evaluation by objective testing. Because mfERG testing is an objective test that evaluates function, it may be used in place of visual fields. Amsler grid testing is no longer recommended. Fundus examinations are advised for documentation, but visible bull's-eye maculopathy is a late change, and the goal of screening is to recognize toxicity at an earlier stage. COUNSELING: Patients should be aware of the risk of toxicity and the rationale for screening (to detect early changes and minimize visual loss, not necessarily to prevent it). The drugs should be stopped if possible when toxicity is recognized or strongly suspected, but this is a decision to be made in conjunction with patients and their medical physicians.

Abstract

Conventional photographs do not show how, at any moment of visual fixation, neural vision is clear only in the foveal center. We have developed new computer simulations to show both normal vision and vision with macular disease. These simulations show the nature of momentary vision for life tasks such as reading, facial recognition, and walking in the street. They also dramatically show the impact of macular disease (with scotomas and visual distortion), as there is no surrounding region of clarity. We hope these images will be instructive to both physicians and patients.

Abstract

Sildenafil can cause transient, mild ERG changes in healthy individuals taking large single doses. Although the drug was originally intended for intermittent use in erectile dysfunction, it has now been approved for chronic use in subjects with pulmonary arterial hypertension (PAH). The purpose of our study is to investigate possible ERG changes in subjects using large doses of sildenafil on a chronic daily basis.We examined five subjects with PAH taking sildenafil daily for 1-4 years. Full-field electroretinogram (ERG), multifocal ERG (mfERG), and color testing were performed. Three of the subjects returned on a later date for challenge off and on the medication.On chronic daily sildenafil, color vision testing was normal, and ERG and mfERG amplitudes were normal; however, cone implicit times on drug were modestly lengthened. There were no consistent full-field ERG changes when off the drug, but the mfERG showed a small amplitude increase and implicit time decrease, which returned 1 h after re-dosing.There was a modest lengthening of cone implicit time on chronic daily doses of sildenafil and a hint that some of these changes may be reversible in the short term. It does not appear that chronic sildenafil usage at these dosage levels is seriously toxic or threatening to vision.

Abstract

Retinal stimulation with high spatial resolution requires close proximity of electrodes to target cells. This study examines the effects of material coatings and 3-dimensional geometries of subretinal prostheses on their integration with the retina. A trans-scleral implantation technique was developed to place microfabricated structures in the subretinal space of RCS rats. The effect of three coatings (silicon oxide, iridium oxide and parylene) and three geometries (flat, pillars and chambers) on the retinal integration was compared using passive implants. Retinal morphology was evaluated histologically 6 weeks after implantation. For 3-dimensional implants the retinal cell phenotype was also evaluated using Computational Molecular Phenotyping. Flat implants coated with parylene and iridium oxide were generally well tolerated in the subretinal space, inducing only a mild gliotic response. However, silicon-oxide coatings induced the formation of a significant fibrotic seal around the implants. Glial proliferation was observed at the base of the pillar electrode arrays and inside the chambers. The non-traumatic penetration of pillar tips into the retina provided uniform and stable proximity to the inner nuclear layer. Retinal cells migrated into chambers with apertures larger than 10 mum. Both pillars and chambers achieved better proximity to the inner retinal cells than flat implants. However, isolation of retinal cells inside the chamber arrays is likely to affect their long-term viability. Pillars demonstrated minimal alteration of the inner retinal architecture, and thus appear to be the most promising approach for maintaining close proximity between the retinal prosthetic electrodes and target neurons.

Abstract

To systematically assess the changes in retinal morphology during the healing of retinal photocoagulation lesions of various clinical grades.Rabbits were irradiated with a 532-nm Nd:YAG laser with a beam diameter of 330 microm at the retinal surface, a power of 175 mW, and pulse durations between 5 and 100 ms. Retinal lesions were clinically graded 1 minute after placement as invisible, barely visible, light, moderate, intense, very intense, and rupture and were assessed histologically at six time points from 1 hour to 4 months.At all pulse durations, the width of the retinal lesions decreased over time. At clinical grades of light and more severe (pulse durations, 10-100 ms), retinal scarring stabilized at 1 month at approximately 35% of the initial lesion diameter. Lesions clinically categorized as barely visible and invisible (pulse durations of 7 and 5 ms) exhibited coagulation of the photoreceptor layer but did not result in permanent scarring. In these lesions, photoreceptors completely filled in the damaged areas by 4 months.The decreasing width of the retinal damage zone suggests that photoreceptors migrating from unaffected areas fill in the gap in the photoreceptor layer. Laser photocoagulation parameters can be specified to avoid not only the inner retinal damage, but also permanent disorganization and scarring in the photoreceptor layer. These data may facilitate studies to determine those aspects of laser treatment necessary for beneficial clinical response and those that result in extraneous retinal damage.

Abstract

Fenretinide is a synthetic retinoid that interferes with the attachment of retinol to retinol binding protein. It may inhibit accumulation of A2E and lipofuscin, and is proposed as therapy for Stargardt disease. It is currently used for cancer therapy, and mild depression of rod function and dark adaptation is a side effect at standard dosage. We studied two youngsters (aged between 12 and 13) receiving high doses as compassionate treatment for neuroblastoma: 800 mg daily for 1 out of every 3 weeks, for roughly 2 years. Goldmann-Weekers dark adaptometry, ISCEV standard ERG and mfERG were performed, and blood was analyzed for vitamin A. Neither child complained of night blindness or showed retinal fundus abnormalities. On initial exam, dark adaptation thresholds were elevated by 3 log units, and there were no detectable rod ERG responses. However, cone responses and mfERG were normal. Retesting one subject 3 months after stopping the drug revealed normal rod thresholds (slightly delayed) and low normal rod ERG responses. Serum vitamin A levels were normal from both subjects, but there is no record of whether the samples were drawn during cycles on or off drug. Our study demonstrates that high dose Fenretinide can suppress rod function quite completely, although serum vitamin A and rod function apparently return to normal or near normal levels rapidly once the drug is stopped. It is intriguing that cone function and access to vitamin A seems largely independent of Fenretinide effects on retinol availability.

Abstract

To elucidate the visual significance of the foveal pit by measuring foveal architecture and function and to reassess use of the term foveal hypoplasia (as visual acuity can vary among patients who lack a pit).We describe 4 patients who lack a foveal pit. Visual acuities ranged from 20/20 to 20/50. Stratus and Cirrus (Carl Zeiss Meditec, Dublin, California) optical coherence tomographs (OCTs) and multifocal electroretinograms were obtained. High-resolution retinal imaging on 2 of the participants was obtained by using a high-resolution Fourier-domain OCT and an adaptive optics flood-illuminated fundus camera.No participants had a visible foveal pit with conventional OCT. Central widening of the outer nuclear layer and lengthening of cone outer segments were seen with high-resolution Fourier-domain OCT. Adaptive optics imaging showed normal cone diameters in the central 1 degrees to 2 degrees. Central multifocal electroretinogram responses were normal.We show that a foveal pit is not required for foveal cone specialization, anatomically or functionally. This helps to explain the potential for good acuity in the absence of a pit and raises questions about the visual role of the foveal pit. Because the term foveal hypoplasia commonly carries a negative functional implication, it may be more proper to call the anatomic lack of a pit fovea plana.

Abstract

(1) To document variability of the full-field ERG within single recording sessions under ISCEV standards. (2) To identify clinical factors contributing to the observed variability.Nine volunteer subjects were studied, aged 19-32 with no history of retinal disease. ISCEV standard ERGs were recorded. Dark-adapted "standard combined" and light-adapted "cone" b-wave amplitudes and implicit times were measured. Multiple flashes were presented at different interflash intervals and after different periods of dark and light adaptation. The stability of the stimulus flash was measured with a photometer.The statistical coefficient of variability was roughly 2.5% for the standard combined b-wave amplitude and 4.5% for the cone b-wave. B-wave implicit times showed a coefficient of variability of 2% for standard combined responses and 1.25% for cone responses. Variation in interflash interval, dark and light adaptation times, and sporadic unusual waveforms influenced measured b-wave amplitudes.Intrasession variability is much lower than previously reported values for intersession variability. Nonetheless, it represents a baseline of variability that will affect results and that may be minimized by recognition and control of contributing factors.

Abstract

A case of late-onset (age 51) visual loss and night-blindness is presented to illustrate the challenges of diagnosis. This patient had anti-enolase antibodies, and demonstrates the importance of auto-immune retinopathy as a potential cause of late-onset retinal "dystrophy."

Abstract

The alcohol-induced electro-oculographic (EOG) response has been proposed by Arden as an indicator of retinal pigment epithelial (RPE) integrity. We have evaluated the consistency of the alcohol-EOG with respect to clinical applicability and compared this response to the ISCEV-standard EOG. We recorded, in a group of normal subjects (n=29, 14 men with mean age 42+/-11 years and 15 women with mean age 36+/-13 years), the alcohol response to a single oral dose of ethanol at 160 mg/kg (as 40 proof vodka, drunk in 15 s after 12 h of fasting), followed by an ISCEV-standard EOG 90 min after alcohol administration. Blood alcohol levels were monitored at regular intervals with a breath analyzer. We found a wide range of amplitudes in both light and alcohol responses among participants, from minimal to large values. Subjects had a wide range of blood alcohol concentrations from 0.02 to 0.10%; near the time of the response peak, but there was no relationship between alcohol levels and peak/baseline ratios. In addition, there was no relationship between alcohol peak/baseline ratio and the Arden ratio. Neither the alcohol nor the light response parameters showed any relationship with age or gender. Some of the inter-individual variability in the EOG response to alcohol may reflect variable absorption of oral alcohol. The alcohol-induced EOG has too broad a range of responses to be useful clinically for the one-time evaluation of individual patients. We have similar concerns regarding clinical applications of the standard light-induced EOG.

Abstract

The human eye is composed of multiple compartments, diverse in form, function, and embryologic origin, that work in concert to provide us with our sense of sight. We set out to systematically characterize the global gene expression patterns that specify the distinctive characteristics of the various eye compartments.We used DNA microarrays representing approximately 30,000 human genes to analyze gene expression in the cornea, lens, iris, ciliary body, retina, and optic nerve. The distinctive patterns of expression in each compartment could be interpreted in relation to the physiology and cellular composition of each tissue. Notably, the sets of genes selectively expressed in the retina and in the lens were particularly large and diverse. Genes with roles in immune defense, particularly complement components, were expressed at especially high levels in the anterior segment tissues. We also found consistent differences between the gene expression patterns of the macula and peripheral retina, paralleling the differences in cell layer densities between these regions. Based on the hypothesis that genes responsible for diseases that affect a particular eye compartment are likely to be selectively expressed in that compartment, we compared our gene expression signatures with genetic mapping studies to identify candidate genes for diseases affecting the cornea, lens, and retina.Through genome-scale gene expression profiling, we were able to discover distinct gene expression 'signatures' for each eye compartment and identified candidate disease genes that can serve as a reference database for investigating the physiology and pathophysiology of the eye.

Abstract

One of the critical difficulties in design of a high-resolution retinal implant is the proximity of stimulating electrodes to the target cells. This is a report of a phenomenon of retinal cellular migration into a perforated membrane that may help to address this problem.Mylar membranes with an array of perforations (3-40 microm in diameter) were used as a substrate for in vitro retinal culture (chicken, rats) and were also transplanted into the subretinal space of adult RCS rats. A membrane was also constructed with a seal on one side to restrict the migration.Retinal tissue in vitro grew within 3 days through perforations of greater than 5 microm in diameter when the membranes were positioned on the photoreceptor side, but no migration occurred if the implant was placed on the inner retinal surface. Histology with light microscopy and transmission electron microscopy (TEM) demonstrated that migrating cells retain neuronal structures for signal transduction. Similar growth of RCS rat retinal cells occurred in vivo within 5 days of implantation. A basal seal kept the migrating tissue within a small membrane compartment.Retinal neurons migrate within a few days into perforations (> 5 microm in diameter) of a membrane placed into the subretinal space. This may provide a means of gaining close proximity between electrodes in a retinal prosthetic chip and target cells, and thus allow a greater density of stimulating elements to subserve higher resolution. Further studies are needed to explore the long-term stability of the retinal migration.

Abstract

We sought to determine whether routine ERGs using ISCEV standard stimuli, would show a pattern of circadian variation. We examined ERGs from 40 successive normal subjects who were tested at different times during regular laboratory operating hours of 9 am to 4 pm, and also reviewed high intensity a-waves from a subgroup. There were no obvious associations of either ERG amplitude or implicit time with time of day. No statistically significant difference was found between average ISCEV ERG parameters or high-intensity a-wave parameters obtained in the morning (9 am to 1 pm) and afternoon (1 pm to 4 pm). We conclude that time of day is not critical for routine ERG recordings, although small, variable, circadian changes may well be present. We suggest that the time of day be noted on clinical recordings, in case this information becomes relevant for a particular patient.

Abstract

Current neural prostheses use electricity as the mode of stimulation, yet information transfer in neural circuitry is primarily through chemical transmitters. To address this disparity, this study was conducted to devise a prototype interface for a retinal prosthetic based on localized chemical delivery. The goal was to determine whether fluidic delivery through microfabricated apertures could be used to stimulate at single-cell dimensions.A drug delivery system was microfabricated based on a 5- or 10- microm aperture in a 500-nm thick silicon nitride membrane to localize and limit transmitter release. The aperture overlies a microfluidic delivery channel in a silicone elastomer. To demonstrate the effectiveness of this transmitter-based prosthesis, rat pheochromocytoma cells (PC12 cell line) were grown on the surface of the device to test the precision of stimulation, using bradykinin as a stimulant and measuring fluorescence from the calcium indicator, fluo-4.The extent of stimulation could be controlled accurately by varying the concentration of stimulant, from a single cell adjacent to the aperture to a broad area of cells. The stimulation radius was as small as 10 microm, corresponding to stimulation volumes as small as 2 pL. The relationship between the extent of stimulation and concentration was linear.The demonstration of localized chemical stimulation of excitable cells illustrates the potential of this technology for retinal prostheses. Although this is only a proof of concept of neurotransmitter stimulation for a retinal prosthesis, it is a significant first step toward mimicking neurotransmitter release during synaptic transmission.

Abstract

The Dutch graphic artist, Maurits C. Escher (1898-1972) is famous for intricate and sometimes illusory images which challenge our sensibility. Over many years, from the 1920s to the 1960s, he made designs with interlocking figures that confuse the distinction between object and background. His correspondence and writings suggest that these designs were largely self-created until the 1950s when fame brought him increasingly into contact with scholars from disciplines such as mathematics, crystallography, and psychology. One of these contacts was with an ophthalmologist, Johan W. Wagenaar (1911-), who had been using Escher's designs to illustrate lectures about vision during night driving. A correspondence began that extended for almost a decade and altered Escher's concept of his own work. It is an intriguing footnote to the career of this extraordinary artist.

Abstract

To develop a better and more economical instrument for precise, tractionless, "cold" cutting during intraocular surgery. The use of highly localized electric fields rather than laser light as the means of tissue dissection was investigated.A high electric field at the tip of a fine wire can, like lasers, initiate plasma formation. Micrometer-length plasma streamers are generated when an insulated 25 micron (microm) wire, exposed to physiological medium at one end, is subjected to nanosecond electrical pulses between 1 and 8 kV in magnitude. The explosive evaporation of water in the vicinity of these streamers cuts soft tissue without heat deposition into surrounding material (cold cutting). Streamers of plasma and the dynamics of water evaporation were imaged using an inverted microscope and fast flash photography. Cutting effectiveness was evaluated on both polyacrylamide gels, on different tissues from excised bovine eyes, and in vivo on rabbit retina. Standard histology techniques were used to examine the tissue.Electric pulses with energies between 150 and 670 microJ produced plasma streamers in saline between 10 and 200 microm in length. Application of electric discharges to dense (10%) polyacrylamide gels resulted in fracturing of the gel without ejection of bulk material. In both dense and softer (6%) gels, layer by layer shaving was possible with pulse energy rather than number of pulses as the determinant of ultimate cutting depth. The instrument made precise partial or full-thickness cuts of retina, iris, lens, and lens capsule without any evidence of thermal damage. Because different tissues require distinct energies for dissection, tissue-selective cutting on complex structures can be performed if the appropriate pulse energies are used; for example, retina can be dissected without damage to the major retinal vessels.This instrument, called the Pulsed Electron Avalanche Knife (PEAK), can quickly and precisely cut intraocular tissues without traction. The small delivery probe and modest cost make it promising for many ophthalmic applications, including retinal, cataract, and glaucoma surgery. In addition, the instrument may be useful in nonophthalmic procedures such as intravascular surgery and neurosurgery.

Abstract

No "major" painter is known to be color deficient. Are there truly no color deficient artists, or have they not been recognized? The historical literature cites criteria for recognizing color deficiency in artists, but they are hard to apply without knowing the intentions of an artist. The work and commentary of a color-deficient artist who works currently in Paris are presented as an example. He uses a limited palette of colors, based on advice from colleagues as much as his own perceptions, and he uses colors in ways that do not always fit with expectations for color deficiency. Biographies of earlier painters suggest that there were a few whose color sense was poor, but these painters used assistants to help. The color sense of others, such as the English landscape painter John Constable (1776-1837), has been questioned because of a preponderance of suspicious color, such as murky green. However, there are good reasons to doubt that Constable was color deficient. It is instructive to know how proven color deficiency has influenced an artist's style. When medical information is unavailable, the best advice for the diagnostically-inclined observer is just to enjoy the art.

Abstract

To examine results of the multifocal electroretinogram (MERG) after spontaneous resolution of central serous chorioretinopathy (CSC) detachments.Multifocal electroretinograms were recorded from both eyes of 5 recovered patients with CSC and 10 age-matched healthy subjects. All patients with CSC had bilaterally subnormal MERG amplitudes during a first attack of CSC occuring 7 to 23 months earlier.After recovery from CSC, MERG A-wave and B-wave amplitudes increased markedly where the detachment resolved, and moderately elsewhere in the posterior pole of both eyes. However, the signals from both eyes remained either subnormal or low-normal relative to controls. Multifocal electroretinogram B-wave latencies improved from prolonged to mid-normal values in both eyes.Both eyes of patients with active unilateral CSC exhibit diminished MERG amplitudes. Although MERG response amplitudes increased modestly after recovery from CSC, they remained statistically subnormal throughout the posterior pole of both eyes. These findings support the theory that subretinal fluid retention in CSC is secondary to diffuse pathologic changes in the choroid and/or retinal pigment epithelium. They also suggest that the underlying or predisposing abnormalities of CSC resolved only partially in our patients. Components of the MERG may have value as a prognostic tool for judging the risk of developing symptomatic CSC. Arch Ophthalmol. 2000;118:1211-1215

A brief history of macular grids: From Thomas Reid to Edvard Munch and Marc AmslerSURVEY OF OPHTHALMOLOGYMarmor, M. F.2000; 44 (4): 343-353

Abstract

Metamorphopsia is a symptom of retinal distortion from intrinsic retinal disease. It has undoubtedly been experienced for millennia, but its clinical significance has been appreciated only in modern times. The Norwegian painter Edvard Munch recognized scotomas and metamorphopsia after suffering an intraocular hemorrhage in his 60th year. Drawings made during this illness show his changing perceptions, and also his attempts to document them with a grid of lines. The Scottish philosopher Thomas Reid may have been the first to write about metamorphopsia. He described distortion of his vision in 1764, after an episode of sungazing, and recognized that the problem was probably of retinal origin. Lines or grids to document metamorphopsia have appeared in ophthalmology textbooks for more than 100 years, but testing for macular degeneration did not become routine until the dissemination of Amsler's grids in the middle of the 20th century. This is in large measure a result of developments in ophthalmology that made therapy for macular disease possible.

Abstract

Sildenafil citrate (Viagra) is a new oral medication that inhibits phosphodiesterase-5 (PDE5) in the corpus cavernosum to facilitate penile erection for the treatment of male impotence. The drug also has a mild inhibitory effect on PDE6, which controls the level of cyclic guanosine monophosphate in the retina, and it may cause a perception of bluish haze or increased light sensitivity in some patients. Long-term retinal damage has not been reported, but long-term electroretinographic studies have not been performed. Sildenafil causes a mild lowering of blood pressure and is absolutely contraindicated in patients taking any form of nitrate medication. A number of cardiovascular deaths and retinal vascular events in patients taking sildenafil have been reported, but so far the rate of these complications does not exceed expectation for an elderly population. Ophthalmologists should alert patients to the ocular side effects and potential risks of this new drug until further clinical experience has been obtained.

Abstract

George K. Kambara has been a leader in ophthalmic education and practice on the West Coast. His choice of ophthalmology arose in part because of his experience running an eye, ear, nose, and throat clinic while interned as a Japanese American during World War II. His training took him from San Francisco, to the Tule Lake Relocation Center, to the Memphis Eye, Ear, Nose and Throat Hospital, to the University of Wisconsin, and eventually back to Los Angeles. He saw both sides of discrimination, as a Japanese American in California and as a "white" in the South. He was turned down for positions that he should have had based on his education, but he was also supported by many individuals who put aside public fears to help him. His story shows a triumph of the spirit, but is also a reminder of dark times that should not be forgotten.

Abstract

To investigate the topography of cone electroretinographic (ERG) responses in the enhanced S cone syndrome (ESCS).A 19-year-old female with ESCS who was one of the original cases defining the syndrome was studied. Full-field, focal (Maculoscope) and multifocal (VERIS) ERGs were performed using white light. Multifocal ERG responses were also generated with red and blue stimuli and with a slow m-sequence to elicit off-responses. Results were analyzed by averaging data in rings at increasing eccentricity from the fovea and compared to data recorded identically from a normal subject.The full-field ERG from this patient showed typ ical large slow photopic waveforms and was unchanged from recordings made 9 years earlier. The focal ERG showed signals of borderline low amplitude from the fovea with the multifocal ERG, the ESCS responses from the central macula had a relatively normal waveform, and those 9 degrees to 20 degrees from fixation showed the prolonged wave-form that characterizes the full-field ERG. Responses were larger to blue light than red light in ESCS in both center and periphery. The central ESCS responses were relatively normal in timing to both red and blue light, whereas the peripheral ESCS responses were markedly delayed to both. Off-responses were seen in ESCS only near the foveal center.The marked differences between central and peripheral ERG responses in ESCS suggest that there are different distributions of S, L, and M cones in these regions and that S cones may feed into different neural pathways in the center and periphery. It was postulated that in ESCS, S cones may partially replace L and M cones centrally and feed into the usual S cone pathways. In the periphery, however, there is little L and M cone b-wave activity in ESCS, and S cones may usurp both the space and neural pathways of the rods.

Abstract

Little information is available on the long-term course of pattern dystrophies, although some older individuals have been observed with macular atrophy. We sought to evaluate the evolution of symptoms, fundus changes, and physiologic findings by re-examining a family with pattern dystrophy after 20 years.Four patients of seven initially examined were reevaluated 20 years later; two additional affected family members over age 60 were studied for the first time. Patients' current ages ranged from 38 to 73 years. Comprehensive ophthalmic examinations were supplemented with fluorescein angiography, dark adaptometry, color vision, electroretinography, and electrooculography.During the 20-year interval, visual acuity remained stable and 20/40 or better in all patients. One 62-year-old patient developed paracentral scotomas. All fundi showed evolution of pigmentary changes and increasing atrophy of pigment epithelium and choriocapillaris in the macula. Electro-oculograms were originally subnormal in all patients and changed very little. Electroretinograms, initially normal in two patients, became borderline or mildly subnormal and slightly reduced in the two patients first examined after age 60.Pattern dystrophy in this family was associated with minimal diminution of visual function during a 20-year interval. However, there was electroretinographic evidence of mild diffuse photoreceptor damage in the older patients, and geographic macular atrophy was prominent (suggesting a risk of vision loss in old age). Some cases of atrophic, age-related macular degeneration may represent an evolution of pattern dystrophy.

Abstract

To investigate the source and protein content of sub-retinal fluid in self-forming experimental serous retinal detachments.Detachments were induced in Dutch rabbit eyes using rose bengal photosensitization to cause choriocapillaris injury and thrombosis. Serous detachments formed spontaneously within the next 24 h. Subretinal fluid was withdrawn 2, 8 and 24 hrs after photosensitization, and was analyzed for osmolality and albumin content by gel electrophoresis.The albumin concentration in the subretinal fluid of light-induced detachments was 68% of serum level at 3 h after light damage, and rose close to serum level by 24 h. The osmolality of subretinal fluid 24 h after light damage was essentially the same as serum and vitreous fluid.The subretinal protein and fluid in light-induced detachments in the central retina of the rabbit must come from the choroid, since there are no intrinsic retinal blood vessels in that region of the fundus. These data demonstrate that serous retinal detachments can form from choroidal fluid.

Abstract

To determine the oxygen and glucose dependency of retinal adhesion in primate and rabbit.Experiments were performed on Dutch rabbits and monkeys. Retinal adhesiveness was measured by peeling the retina from the retinal pigment epithelium in vitro, under different conditions of PO2 and glucose supply, and by observing the amount of adherent pigment. In vivo ischemia was produced by raising the intraocular pressure.Retinal adhesion failed quickly at low oxygen tensions, but a well-oxygenated solution preserved strong retinal adhesion in vitro for 15 to 20 minutes in rabbit tissue and up to 50 minutes in primate tissue. Ischemic adhesive failure was reversible on raising the PO2. Glucose levels did not affect adhesiveness. Ischemia in vivo for more than 1 minute caused rabbit retina to lose its adhesiveness.Retinal adhesion is continually and reversibly dependent on oxygenation, and probably on aerobic metabolism. Primate tissue is more resistant to metabolic adhesive failure than is rabbit tissue, but the metabolic requirements appear qualitatively similar.

Abstract

To evaluate experimentally the conditions necessary for the formation of serous detachments.Selective injury to the retinal pigment epithelium (RPE) and choriocapillaris was produced in cats using weak laser burns and intense diffuse light, with or without photosensitization with rose bengal. The fundi were analyzed by observation, fluorescein angiography, and histologic examination.Injuring the RPE alone did not cause detachments. Focal injury to the RPE and choriocapillaris caused moderate detachment only when an area surrounding the focal leakage site had been subjected to light damage. Diffuse injury to the RPE and choriocapillaris caused broader detachments.Three conditions are necessary for serous detachments to form: (1) a source of fluid pressure, (2) a defect in the blood-retinal barrier (entry site), and (3) an area of impaired fluid transport beyond the site of leakage (if fluid is to accumulate over a broader area).

Abstract

To determine factors that influence retinal adhesion in the primate and compare these with previous data from the rabbit.Retinal adhesiveness was studied in monkey eyes immediately after enucleation. The retina was peeled manually from the retinal pigment epithelium, and the amount of pigment that remained adherent to the retina was used as an index of adhesiveness.The rate of post mortem failure of retinal adhesiveness in the monkey was less than in the rabbit under similar conditions. However, as in the rabbit, adhesiveness was sensitive to temperature, pH, and the concentrations of calcium and magnesium, and subretinal injections of neuraminidase weakened adhesion beyond the injection sites.Mechanisms of retinal adhesion are similar in primates and rabbits.

Abstract

Normal retina is firmly attached to the retinal pigment epithelium, but the force of this adhesion drops precipitously within the first 2-3 min after enucleation. The purpose was to study metabolic factors that might be relevant to this postmortem failure of adhesion.Dutch rabbit retina was manually peeled from the retinal pigment epithelium on strips of enucleated eyecup within a 37 degrees C bath. Retinal adhesiveness was measured by observing the amount of retinal pigment epithelium that remained adherent to the retina.Autologous whole blood in place of salt solution retarded the decrease in adhesiveness. A solution of hemoglobin alone was similarly effective, whereas methemoglobin solution failed to help the persistence of retinal adhesion. Bubbling oxygen into the salt solution and circulating it to avoid oxygen depletion at the tissue boundary also proved effective at sustaining retinal adhesiveness. Eyes made ischemic in vivo for 5 min or longer, by elevating intraocular pressure, showed virtually no retinal adhesion when enucleated immediately thereafter. However, eyes made ischemic for 10 min, but allowed to regain circulation for 5 min before enucleation, showed a return of retinal adhesiveness to 80% of normal.Oxidative metabolism is critical to the maintenance of retinal adhesiveness, and the effects of oxygen deprivation on adhesion are reversible within a certain time period.

Abstract

The electro-oculogram is a widely used electrophysiological test, but recording techniques vary among different laboratories. This standard, approved by the International Society for Clinical Electrophysiology of Vision (ISCEV), describes simple technical procedures that will allow reproducible and comparable electro-oculograms to be recorded under a few defined conditions. The document is intended to improve the comparability of electro-oculographic data obtained throughout the world by guiding both clinicians and manufacturers, and the ISCEV recommends that future published reports indicate whether the recording technique meets the international standard.

Abstract

We studied the recovery of retinal pigment epithelium and retinal function after 80 minutes of pressure-induced ischemia in rabbits. Just before restoring circulation, we gave intravenous mannitol (an osmotic agent and free-radical scavenger), dextromethorphan (an N-methyl-D-aspartate receptor antagonist), or catalase (an antioxidant enzyme). Mannitol has not previously been shown to be protective for retinal or retinal pigment epithelial ischemia. At 24 hours after reperfusion, the electroretinogram b-wave was reduced to 37% of preischemic amplitude in untreated eyes, but it recovered to 67% to 80% after treatment with all three agents. The c-wave was replaced by a negative slow PIII response in control eyes and in seven of 12 catalase-treated eyes, but it recovered by 58% to 82% in the remaining catalase-treated eyes and all the mannitol- and dextromethorphan-treated eyes. Histologic examination confirmed that retinal pigment epithelium as well as retina had been damaged by the ischemia. The effects of mannitol seem of special interest, since the drug has a dual mechanism of action and is clinically available.

Abstract

Small retinal detachments (blebs) were made in living eyes by injecting balanced salt solution into the subretinal space with a micropipette. A second micropipette, inserted into the same bleb, measured subretinal pressure using a resistance servonulling system. The adhesive force was calculated from the pressure difference across the retina according to Laplace's law. The retinal adhesive force in rabbit, cat, and monkey eyes averaged 1.0, 1.8, and 1.4 x 10(2) dyne/cm, respectively. In rabbit eyes, 2 hr after intravenous administration of 15 mg/kg acetazolamide, the retinal adhesive force was increased to 133%. In monkeys, this dose of acetazolamide increased retinal adhesion to 144% of control values. Mannitol (2 g/kg) increased retinal adhesion in the monkey to 153% of control values 90 min after intravenous injection (compared with an increase of 145% in previous experiments in the rabbit). Because both mannitol and acetazolamide enhance retinal adhesiveness in living primate eyes, it seems likely that they will have a similar effect in humans that they may be clinically useful.

Abstract

Retinal adhesiveness in vitro is reduced by lowering the external calcium (Ca2+) concentration. The effects of lowering subretinal Ca2+ concentration in living rabbit eyes was investigated by making experimental retinal detachments (blebs) filled with Ca(2+)-free disodium edetate solution. Unlike blebs made with Hanks' solution, these low-Ca2+ blebs enlarged progressively after they were formed, and they were surrounded by a wide whitish halo. This halo region had weak adhesion (shown by the rapid spread of fluorescein solution into the halo and by the measurement of local adhesiveness after enucleation). The retinal pigment epithelial microvilli in the halo appeared stretched toward the center of the blebs as if there had been retinal traction or movement. Measurements of retinal adhesiveness in vivo showed it to be decreased to about 30% of normal by use of this solution.

Abstract

South East (SE) Asians accounted for a disproportionate percentage of the functional visual loss (FVL) seen in our area between 1983 and 1987. Moreover, 94% of the SE Asian FVL patients were Cambodian, although Cambodians only represented 20-30% of the local SE Asian patient population. Cambodian refugees are, at present, generally from lower socio-economic classes than the Vietnamese, and a much larger percentage of them have a history of camp incarceration and previous trauma. The Cambodians presenting with FVL may have conversion hysteria influenced by their wartime experience and cultural background. This study demonstrates that the SE Asian refugees in California are not a homogenous group with respect to visual problems, and that an awareness of cultural or historical factors can be important to the management of ophthalmic symptoms in our multi-cultural societies.

Abstract

Thioridazine toxicity has been described as a 'progressive chorioretinopathy', but this designation can be misleading. During the first year after thioridazine exposure retinal pigmentation evolves from a granular to a patchy or nummular appearance. However, visual function and the electroretinogram typically improve during this period. Some cases may show chorioretinal atrophy and functional loss many years later, but there is little evidence for ongoing drug-related progression. Late atrophy may represent degeneration of cells that were injured subclinically at the time of initial drug exposure. Although thioridazine toxicity produces an evolving pigmentary disturbance, functional changes must be monitored independently of fundus appearance.

Abstract

The role of interphotoreceptor matrix (IPM) constituents in mediating adhesion between the retina and retinal pigment epithelium (RPE) was investigated by injecting specific enzymes into rabbit eyes either intravitreally or subretinally. Retinal adhesiveness was measured by peeling the retina from the pigment epithelium 1-3 days later and observing the amount of adherent pigment. Effects of enzymes on the IPM were monitored by observation of peanut agglutinin (PNA) binding to cone matrix sheaths; retinal and RPE toxicity was excluded by electroretinography and histology. Three enzymes that degrade glycosaminoglycans or saccharides known to be constituents of the IPM (chondroitinase ABC, neuraminidase, and testicular hyaluronidase) both weakened adhesion and altered PNA binding, although the effects on the cone matrix sheaths were different for each enzyme. An enzyme specific for hyaluronic acid (Streptomyces-derived hyaluronidase), which has not been identified as a major IPM constituent, had no effect on either adhesion or PNA binding. The authors conclude that IPM-associated glycoconjugates participate in retinal adhesion, although their precise composition, interaction with IPM components, and relationship to other mechanisms of adhesion remain to be determined.

Abstract

We studied eight patients who had night blindness, maculopathy (often cystoid), degenerative changes in the region of the vascular arcades, relatively mild visual field loss, and an unusual but characteristic electroretinogram. The dark-adapted electroretinogram showed no response to low-intensity stimuli that normally activate the rods, but large, slow responses to high-intensity stimuli. These large, slow waveforms persisted without change under light adaptation, and showed a striking mismatch to photopically balanced short and long wavelength stimuli (with sensitivity much greater to short than long wave-lengths). Since there is evidence from other studies that the electroretinogram and psychophysical responses represent hypersensitivity of short wavelength-sensitive (S or blue) cones, we propose that this disorder be called the enhanced S cone syndrome. There can be different degrees of severity in this syndrome, and progression appears to be slow.

Abstract

Fundus albipunctatus (FA) is considered to be a congenital stationary night-blinding disorder, but there has been no electrophysiologic or photographic documentation of long stability or change. This documentation is presented for two cases followed for 13 to 14 years. The physiologic (functional) deficits appeared to be stable, in support of the concept that FA is not a progressive dystrophy. However, the fundus lesions evolved in appearance from flecks in childhood to relatively permanent punctate dots that increase in number over the years.

Abstract

Experimental work shows that subretinal fluid is removed both by active transport across the retinal pigment epithelium (RPE) and by passive hydrostatic and oncotic forces that work most effectively when the RPE barrier has been damaged. The retina will stay attached whether or not the RPE is intact--but retinal function requires the RPE barrier and thus active transport is the primary mechanism of subretinal fluid control. RPE fluid transport is normally limited by the retina (which resists water flow from the vitreous) but can be quite powerful when a reservoir of subretinal fluid is present. Clinical serous detachments are unlikely to form solely as a result of small RPE defects or leaks, since the active and passive transport systems for removing subretinal fluid are both so strong. It is suggested that the primary pathology in most serous retinopathy is a diffuse metabolic or vascular abnormality of RPE fluid transport, and that RPE defects or leaks are necessary but only secondary components of the disease. Several hypotheses for removing subretinal fluid therapeutically are considered in terms of their physiology. The subretinal space between the photoreceptors and the retinal pigment epithelium (RPE) is the remnant of the embryonic optic vesicle. In the developed eye the subretinal space is of minimal size, but no tissue junctions form across it and it can re-open under pathological conditions of retinal detachment. In a sense, the title of this paper is misleading since normally there should be no subretinal fluid to control. However, ocular mechanisms are necessary to prevent an accumulation of fluid, and to remove it under conditions of stress or disease.

Abstract

Retinal ischemia was induced in rabbits by increasing intraocular pressure above systolic blood pressure for 60 or 75 minutes, and retinal function was monitored by electroretinography. Pretreatment with intravenous dextromethorphan, a nonprescription antitussive and selective antagonist of N-methyl-D-aspartate receptors, enhanced greatly the post-ischemic recovery of b-wave amplitude. Dextromethorphan may prove to be useful clinically in the management of retinal ischemic disease.

Abstract

Photoaversion, or light-induced interference with visual comfort and performance, has been a recognised but poorly documented symptom in retinitis pigmentosa (RP). We found that a majority of our RP patients complained of photoaversion even in the absence of significant cataract. RP patients had reduced contrast sensitivity relative to normal people, but the decrement in their visual performance as a result of glare or photostress was only slight. RP patients had raised short-term adaptation and increment threshold levels, but their rate of short-term or photopic adaptation was normal. Photoaversion in RP may result because a small interference with contrast sensitivity or adaptation can place patients in a range of functional disability, or it may derive from a combination of minor aberrations.

NEW HYPOTHESES ON THE PATHOGENESIS AND TREATMENT OF SEROUS RETINAL-DETACHMENTGRAEFES ARCHIVE FOR CLINICAL AND EXPERIMENTAL OPHTHALMOLOGYMarmor, M. F.1988; 226 (6): 548-552

Abstract

Recent experimental work has shown that, under normal conditions, most subretinal fluid is absorbed rapidly by active transport across the retinal pigment epithelium (RPE). However, in the presence of damage to the RPE blood-retinal barrier, subretinal fluid is rapidly cleared by passive forces. Thus, it is apparent that RPE defects do not by themselves cause serous retinal detachment. A hypothesis is presented that some serous detachments occur because normal metabolic transport systems of the RPE have been damaged, while the blood-retinal barrier remains intact to prevent passive drainage of the subretinal space. Under these conditions, a focal RPE "leak" can overload the system so that the serous fluid accumulates and persists. Photocoagulation of a leaking point can facilitate resolution of the fluid, but as long as the underlying metabolic dysfunction of the RPE persists, recurrence is possible. Some forms of serous detachment may thus be viewed as diffuse rather than focal ocular disorders in which the transport capability of the RPE has been damaged; such damage can result from systemic pathology such as adrenergic stress (e.g., central serous chorioretinopathy) or vascular disease (e.g., hypertension).

The membrane of giant molluscan neurons: electrophysiologic properties and the origin of the resting potential.Progress in neurobiologyMarmor, M. F.1975; 5 (2): 167-195

Abstract

The molluscan neuron, because of its large size and accessibility, has been an important model for studying the electrophysiology of nerve cells. This review catalogs data about specific molluscan neurons, but the greater importance of this material is in the broad picture of how a neuronal membrane maintains internal potential and is responsive to changes in the environment. Electrical properties of the membrane. The mechanisms which contribute to the resting potential in molluscan neurons can be separated into ionic and metabolic components. When the electrogenic sodium pump is eliminated experimentally, the ionic component of the potential follows the constant field equation quite closely. Many of the "constants" and "parameters" which characterize the membrane of molluscan neurons are actually variables which depend upon temperature, ionic environment, and membrane potential. The evaluation of the electrical parameters is complicated by extensive infoldings of the somatic membrane, and by large axons which drain current from the soma. Most molluscan neurons have a very high specific membrane resistance and a correspondingly low potassium permeability. Membrane capacitance is close to the 1 microF/cm2 value which characterizes biological membranes. The current-voltage relation of molluscan neurons may be complicated by inward-going rectification, but if that is inhibited the I-V curve follows the prediction of either the constant field equation or a simple electrical model. Factors which modify membrane behavior. The resting potential of molluscan neurons is very sensitive to changes in temperature and Ko, through a combination of effects upon the electrogenic sodium pump, inward-going rectification, and the membrane "parameters". Inward-going rectification depends upon a rectifying K conductance, and can be eliminated by cold or the removal of Ko. Strong or prolonged currents have time-dependent effects upon the membrane, and excessive polarization leads to a "high conductance state". The underlying (non-rectifying) K permeability of the membrane is relatively insensitive to temperature and ionic changes, whereas the Na permeability increases with warming. Membrane resistance varies with both temperature and ions (because the I-V curve is sensitive to these conditions) but membrane capacitance is relatively insensitive to external factors. Electrogenic sodium transport. Sodium transport is electrogenic in molluscan neurons. It can be stimulated by warm temperatures and an excess of substrate (e.g. high Nai); it can be inhibited by cold, by an absence of substrate (e.g. low Ko), or by pharmacologic agents such as cyanide or ouabain.(ABSTRACT TRUNCATED AT 400 WORDS)

Conference Proceedings

Abstract

This paper reviews the anatomic and physiologic conditions which predispose to fluid accumulation within the retina. Retinal edema has its inception in disease that causes a breakdown of the blood-retinal barrier in retinal capillaries and/or the retinal pigment epithelium (RPE). Edema develops not only because protein and fluid enter the extracellular space, but because the external limiting membrane and the convoluted extracellular pathway within the retina limit the clearance of albumin and other large osmotically-active molecules. These molecules bind water to cause edema. Recognition of edema clinically is complicated by the facts that angiographic markers (fluorescein and ICG) do not match albumin in size, and that clinical leakage does not always correlate closely with tissue swelling or functional loss. Active water transport across the RPE is efficient at removing subretinal water, but the flow resistance of the retina limits RPE access to the water of retinal edema. Consideration of the pathophysiology of retinal edema may aid in the development of better strategies for managing retinal edema.